The presently available pharmacotherapies for opiate addiction are orally active mu agonists (methadone, LAAM) and a mu antagonist (naltrexone). Bupre-norphine, a mu partial agonist, is intermediate between the two classes, having some advantages over both. Recently we have discovered a series of 14-cinnamoylamidocodeinones having mu partial agonist profiles that are converted metabolically into very long-lasting antagonist morphinones. It has been suggested that the codeinones could be used as treatments for opiate dependence by providing limited reinforcing effects followed by a longer period of opiate blockade. Since it may not be desirable to block mu receptors for protracted periods with an irreversible antagonist, it is proposed to prepare and evaluate similar codeinones and morphinones in which the C/14 substituents are non- electrophilic but in other respects are structurally analogous the cinnamoylamido group in prototype series. The extensive tissue availability of esterases also makes the search for partial agonist esters which can be metabolized to antagonist alcohols, a viable objective. The activity of the target partial agonists as drugs to treat opiate dependence will be determined by the extent and rate of their conversion to the active metabolites. These factors will depend on the route of administration. The oral route which is used for treatment drugs would be expected to facilitate metabolism. Thus in the evaluation procedure promising partial agonist candidates will be tested orally, as well as parenterally, and since metabolism is species dependent, rodents and rhesus monkeys will be used. Another potential problem with the proposal is that high brain levels of an antagonist metabolite could block the effects of a subsequent dose of the partial agonist. This possibility will be investigated by studying multiple dosing of a limited number of potential candidates. Where it exists, partial agonism associated with N-methyl substitution in the piperidine ring of opioid structures is of the mu-type. Such N-methyl derivatives may also have irreversible agonist properties. It is proposed to look for these characteristics in cinnamoyl derivatives of 14 beta- aminodihydromorphinone and oxymorphone.